N-phenyl amidines

ABSTRACT

N-PHENYL AMIDINES WHICH HAVE DIURETIC, ANTITHROMBOGENIC, SMOOTH MUSCLE RELAXANT AND ANTI-INFLAMMATORY PROPERTIES HAVE BEEN DISCOVERED. THEY ARE PREPARED BY REACTING A SUBSTITUTED ANILINE WITH ACARBOXAMIDE SELECTED FROM THE GROUP CONSISTING OF AMIDES AND LACTAMS IN THE PRESENCE OF PHOSPHORUS OXYCHLORIDE. TYPICAL EXAMPLES OF SUBSTITUTED N-PHENYL AMIDINES THUS OBTAINED ARE 5-METHYL2-(N-PHENYLBENZYLAMINO) - PYRROLINE, 2-(N-PHENYLBENZYLAMINO) -1- PYRROLINE AND 3-((N-1-PYRROLINE-2-YL-PANISIDINO)METHYL)INDOLE, INDOLE SUBSTITUTED N-PHENYL AMIDINES CAN BE REARRANGED TO PROVIDES IMINOPYRROLINDINYLINDOLES WHICH ARE USEFUL AS DIURETIC, ANTITHROMBOGENIC AND SMOOTH MUSCLE RELAXANT AGENTS. IN THE CASE OF 3-(N-1PYRROLINE-2-YL-P-ANISIDINO)METHYL)INDOLE, THE REARRANGED PRODUCT IS 3- ((2-(P-METHOXYPHENYLININO)-1-PYRROLINDINYL)METHYL)INDOLE.

United States Patent C) 3,816,454 N-PHENYL AMIDINES Yao-Hua Wu, andWalter G. Lobeck, Evansville, Ind., assignors to Mead Johnson & Company,Evansville,

Ind.

No Drawing. Continuation-impart of abandoned application Ser. No.47,589, June 18, 1970. This application May 22, 1972, Ser. No. 255,701

Int. Cl. 007d 27/56 US. Cl. 260--326.15 9 Claims ABSTRACT OF THEDISCLOSURE N-phenyl amidines which have diuretic, antithrombogenie,smooth muscle relaxant and anti-inflammatory properties have beendiscovered. They are prepared by re acting a substituted aniline with acarboxamide selected from the group consisting of amides and lactams inthe presence of phosphorus oxychloride. Typical examples of substitutedN-phenyl amidines thus obtained are -methyl- 2 (N-phenylbenzylamino)l-pyrroline, Z-(N-phenylbenzylamino) 1 pyrroline and3-[(N-1-pyrrolin-2-yl-panisidino)methyl]indole. Indole substitutedN-phenyl amidines can be rearranged to provide iminopyrrolindinylindoleswhich are useful as diuretic, antithrombogenic and smooth musclerelaxant agents. In the case of3-[(N-lpyrrolin-2-yl-p-anisidino)methy1]indole, the rearranged productis 3 [(2-(p-methoxyphenylimino)-1-pyrrolindinyl)methyl]indole.

CROSS-REFERENCE TO RELATED APPLICATION This application is acontinuation-in-part of copending application Ser. No. 47,589, filedJune 18, 1970 now abandoned.

BACKGROUND OF THE INVENTION A new class of amidines havingpharmaceutical properties is the subject of the present invention.Administration of these substances to mammals produces diuretic andantithrombogenic effects therein.

Diuretics can be grouped according to their molecular structure intofour general classifications. They are, in their chronological order ofintroduction as therapeutics, organomercurial compounds, carbonicanhydrase inhibitors, thiazides typified by 6 chloro 7 sulfamoyl-1,2,4-benzothiadiazine-l,l-dioxide (chlorothiazide), and a miscellaneous groupof chemically unrelated compounds. Among the miscellaneous group ofcompounds are: 4- chloro-N-furfuryl 5 sulfamoylanthranilic acid(furosemide), 2,4,7 triamino-G-phenylpteridine (triamterene) and certainsteroid compounds which are aldosterone antagonists. As a chemicalclass, the N-phenylamidines of the present invention differ structurallyfrom the aforementioned classes of diuretic agents.

The principal function of a diuretic is to reduce the volume ofextracellular fluid in order to eliminate edema or prevent itsdevelopment. Along with the enhancement of the urinary excretion ofwater, diuretics generally produce an elimination of electrolytes suchas sodium, chloride, potassium, and bicarbonate ions. In many instances,as will the thiazides, there is a non-selective elimination ofelectrolytes and electrolyte imbalance results, particularly withrespect to potassium depletion which leads to muscular weakness.

SUMMARY OF THE INVENTION This invention relates to N-phenyl amidines ofFormula I and non-toxic pharmaceutically acceptable acid addition saltsthereof.

3,816,454 Patented June 11, 1974 Formula I These substances, which arecharacterized by Formula I, are new compositions of matter and areuseful as diuretic agents in mammals. In addition, they are useful asantithrombogenic agents, smooth muscle relaxants, and antiinflammatoryagents.

In Formula I, Alk represents an alkylene radical containing 1 or 2carbon atoms such as methylene (-CH ethylene (-CH CH and 1,1-ethylene(omilin).

The X and Y substituents are independently selected from the groupconsisting of hydrogen, halogen, trifluoromethyl, lower alkoxy of from 1to 4 carbon atoms inclusive, and lower alkyl of from 1 to 4 carbon atomsinclusive. Halogen substituents include chlorine, bromine, fluorine, andiodine. By the term independently selected" as used herein, it is meantthat the X and Y substituents may or may not be identical.

Z is selected from the group consisting of phenyl, 2- thienyl, 2-furyl,and R and R substituted 3-indole represented by the formula wherein R ishydrogen, lower alkyl or benzyl and R is hydrogen, halogen, preferablybromine, or lower alkoxy. A is a substituent selected from the groupconsisting of an imino moiety represented by:

Q ll] wherein R is lower alkyl of from 1 to 4 carbon atoms inclusive, nis an integer of 1 to 3 and R and R are independently selected from thegroup consisting of hydrogen and lower alkyl of from 1 to 4 carbon atomsinclusive. Among the A substituents which are represented by the N arel-pyrroline; S-methyl-l-pyrroline; 5,5-dimethyl-1-pyrroline;4-methyl-l-pyrroline; B-methyl-l-pyrroline; 3,4,5,6tetrahydro-ZH-azepine; 3,4,5,6-tetrahydropyridine;5,6-dihydro-2H-1,4-thiazine; 5,6dihydro-2H-1,4-oxazine. It is to beunderstood that by the terms lower alkyl and lower alkoxy as usedhereinabove, it is meant that the carbon chains which comprise thesegroups include both straight and branched chain carbon radicals of 1 to4 carbon atoms inclusive. Exemplary of these carbon chain radicals aremethyl, ethyl, propyl, isopropyl, l-butyl, 1- methylpropyl,Z-methylpropyl, and tert.-butyl.

Illustrative of non-toxic pharmaceutically acceptable acid additionsalts of N-phenyl amidines of Formula I are the salts of a variety ofinorganic and organic acids such as sulfuric, phosphoric, hydrochloric,hydrobromic,

hydroiodic, sulfamic, acetic, lactic, maleic, succinic, malic, fumaric,tartaric, citric, gluconic, glutaric, ascorbic, benzoic, cinnamic, andrelated acids.

According to the process of the present invention for the preparation ofcompounds of Formula I, a substituted aniline having the formula isreacted with a carboxamide selected from the group consisting ofcarboxamides of the formulae 0 s HiiNrr-n R R3,

o= (/CHQH 0 0 N N N H H H in the presence of phosphorus oxychloride in asuitable inert organic solvent. The symbols Alk, Z, X, and Y in thesubstituted aniline reactant and R R R and n in the carboxamide reactanthave the meanings hereinabove described for Formula I. Among thesuitable carboxamide reactants are: N-alkylformamides such asN-methylformamide, N-isopropylformamide, N-tert.-buty1formamide,N-butylformamide and the like. Cyclic carboximides (lactams) can also beemployed and include 2-pyrrolidinone, S-methyl-Z-pyrrolidinone,5,5-dimethyl l-pyrrolidinone, e-caprolactam, E-valerolactam,3-ketothiomorpholine, 3-ketomorpholine, 4-methyl-2-pyrrolidinone,3-methyl-2-pyrrolidinone.

In carrying out the process for the preparation of N- phenyl amidines ofFormula I, approximately stoichiometric quantities of substitutedaniline and appropriate carboxamide reactants and phosphorus oxychlorideare mixed together in an inert aprotic solvent. A suitable and preferredsolvent for carrying out the process is 1,2-dichloroethane. Othersuitable solvents such as chloroform, carbon tetrachloride,1,1-dichloroethane, benzene, toluene, hexane and the like may besatisfactorily employed. The mode of addition of the reactant is notcritical in carrying out the process. For example, a solution orsuspension of substituted aniline and a carboxamide in 1,2-dichloroethane can be added to a solution of phosphorus oxychloride orthe sequence of addition may be reversed and a solution of phosphorusoxychloride can be added to a solution of the carboxamide and aniline.Alternative- 1y, phosphorus oxychloride can be first added to theaniline reactant and the carboxamide reactant then added. Anothersuitable adaptation of the process is the combination of phosphorusoxychloride with a carboxamide and the addition of this mixture to theaniline reactant. Combination of the reactants provides an exothermicreaction and external cooling can be employed to moderate the reaction.However, this is not necessary for the successful completion of thereaction. The reaction of a carboxamide with the aniline takes place ina facile manner when the reactants are combined and generally does notrequire prolonged reaction for the formation of the N- phenyl amidinecompounds of Formula I. We prefer to carry out the reaction by theaddition of phosphorus oxychloride in one portion to the mixture of theaniline and carboxamide reactants in 1,2-dichloroethane. Although thereaction may be carried out at temperatures of about -35 C. to 100 C.,it is generally preferred to carry out the combination of the reactantsat room temperature with efficient stirring and to then stir thereaction mixture overnight before isolating the product.

Illustrative of the preferred method for the preparation of thecompounds of Formula I is the addition of phosphorus oxychloride to amixture of N-benzylaniline and S-methyl 2 pyrrolidinone in1,2-dichloroethylene which provides5-methyl-2-(N-phenylbenzylamino)-1-pyrroline.

In the case of the N-phenylamidines of Formula I wherein Z is an indole,we have fQ d that i is 65 f to add an equimolar amount of a tertiaryamine such as triethylamine in carrying out the hereinabove describedprocess. The addition of triethylamine to the reaction mixture is notnecessary for the successful completion of the reaction but is preferredin some instances in order to increase yields and obtain purer products.

The compounds of Formula I are stable in the form of theirpharmaceutically acceptable acid addition salts, e.g. as theirhydrochlorides. As free bases, however, compounds of Formula I wherein Zis R ,R -indole, Alk is methylene and R is hydrogen, rearrange in thepresence of heat or in solvents such as ethanol at reflux temperature toprovide products of the present invention characterized by Formula IIFORMULA II wherein X, Y, R R and R .are as described above. Non-toxicpharmaceutically acceptable acid addition salts of the rearrangedproducts of Formula II can be prepared as described herein for thecompounds of Formula I. It is to be understood that the compounds ofFormula II are considered to be part of the present invention. Theiminopyrrolidinylindoles of Formula II are active diuretic agents andhave antithrombogenic and smooth muscle relaxant properties according tobiological tests described herein.

Conversion of N-phenyl amidine free bases falling within general FormulaI and the iminopyrrolidinylindole free bases characterized by Formula IIto corresponding non-toxic pharmaceutically acceptable acid additionsalts is accomplished by admixture of the base with a selected acid inan inert organic solvent such as ethanol, benzene, ethyl acetate, ether,halogenated hydrocarbon and the like. One preferred method is to treatthe N-phenyl amidine with substantially one chemical equivalent ofethanolic hydrogen chloride in ethanol solution and precipitate the salttherefrom by addition of anhydrous ether.

- The N-phenyl amidine salts of the present invention are generallywater soluble whereas the bases are substantially insoluble in water.

The method hereinabove described for the preparation of the compounds ofFormula I is a modification of a procedure described by H. Bredereck andK. Bredereck, Ber., 94, 2278- (1961); refer to C. A. 55: 27371.According to this reference, a carboxamide such as 2-pyrrolidinone isfirst treated with phosphorus oxychloride in benzene and then withaniline to provide the amidine 2- phenyliminopyrrolidine. This amidineis substantially inactive as a diuretic agent when tested according tothe Lipschitz method discussed below.

The compounds of the present invention are evaluated as diureticsaccording to the method of W. L. Lipschitz, et al., J. Pharmacol. Expt.T herap., 79, 97 (1943). In this method, groups of 8 rats are fasted 18hours prior to the experiment. A control group is hydrated orally with25 ml. per kilogram of body weight of isotonic saline solution which isalso the vehicle used for dosing the test compound. One control groupreceived a dose of 960 mg./kg. of body weight of urea. Animals of othergroups are treated with various doses of the test compound. Immediatelyafter treatment, the animals are placed in metabolism cages (two rats ofthe same group per cage) and maintained without food or water for 5hours. The volume of urine excreted by each pair is determined afterthis period and the pooled urine is analyzed for sodium, potassium, andchloride ions. The

.5 results for the test compounds are expressed as ratios of the volumeof urine or total quantities of electrolytes (i.e., sodium, potassium,and chloride) excreted during the experimental period compared to theurea control group. In this test, the N-phenyl amidines of Formula Iwere orally administered in doses ranging from 2.7 to 25 mg./kg. of bodyweight.

In the Lipschitz test, the results obtained with the N- phenyl amidinesof the present invention clearly indicate that they are orally etfectivediuretic agents. Substantially increased urine flow, sodium, andchloride ion excretion are obtained following oral administration of theN- phenyl amidines of Formula I.

One of the disadvantages associated with diuretics such as the thiazidesis believed to stem largely from increased excretion of potassium ionconcomitant with water elimination. This is overcome with the N-phenylamidines of the present invention, whereby water elimination is obtainedwhile a favorable balance of sodium to potassium ion excretion ismaintained. For example, oral administration of a representativeN-phenyl amidine of Formula I,-methyl-2-(N-phenylbenzylamino)-1-pyrroline hydrochloride to the rat ata dose of 6.25 mg./kg. of body weight when compared to the urea controlgroup affords a ratio of 2.32 for volume excretion, 2.03 for sodium ionexcretion and 0.75 for potassium ion excretion. Thus, the ratio ofsodium ion excretion to potassium ion excretion is 2.03/ 0.75 which isequivalent to a value of 2.7. Hydrochlorothiazide, a well-known diureticagent, at the same dosage has a ratio of sodium to potassium ionexcretion of 1.65. As stated hercinabove, excessive excretion ofpotassium ion may cause an electrolyte imbalance resulting in adverseside effects.

The compounds of Formulas I and II exert their optimum therapeuticeffects at doses ranging from 0.1 to 100 ing/kg. of body weight and, inparticular, diuretic activity when orally administered to mammals innon-toxic doses ranging from about 0.1 to 25 mg/kg. of body weight perday. These substances may be also administered parenterally, but theoral route is preferred as a matter of convenience and ease ofadministration. Oral administration of the N-phenyl amidines to miceprovides ALD values in the range of 50 to 500 mg./kg.

The N-phenyl amidines of 'Formula I may be administered to mammals inthe form of free bases or as one of their non-toxic pharmaceuticallyacceptable acid addition salts. In either form, they may be compoundedand formulated with organic or inorganic solid materials or .liquidswhich are pharmaceutically acceptable carriers to provide pharmaceuticalcompositions of unit dosage form. Preferably, the unit dosage formcomprises a pharmaceutical carrier and the N-phenyl amidine in an amountranging from about 0.1 to 100 mglkg. of body weight of the mammaltreated. An effective dose of the unit dosage form can then beadministered to mammals to elicit diuresis. Pharmaceutical compositionsconsidered within the scope of this invention may take the form oftablets, powder, granules, capsules, suspensions, solutions, and thelike. Suitable pharmaceutical carriers comprise both solids and liquidssuch as corn starch, lactose, calcium phosphate, stearic acid,polyethylene glycol, water, sesame seed oil, peanut oil, propyleneglycol, and so forth.

Evaluation of the compounds of the present invention forantithrombogenic activity is carried out according to a method describedby Born, Nature, 194, 927 (1962) and OBrien, J. Clin. Path, 15, 446(1962). This is essentially a nephelometric method in which the changein turbidity of a specimen of platelet rich blood plasma is measured oncausation of platelet aggregation by addition of a thrombogenic inducingagent such as adenosine diphosphate, epinephrine, or collagen. Thecompounds of the present invention are eifective antithrombogenic agentsaccording to this test at concentrations in the order of about 30 to 100meg/ml.

Smooth muscle relaxant activity of the compounds of the presentinvention can be measured in standard in vitro and in vivapharmacological tests. One such in vitro test is carried out essentiallyas follows. A segment of rabbit ileum is suspended and oxygenated inTyrodes solution and affixed to a tension transducer for electronicrecording of isometric contractions. After controlled responses to astandard dose of a spasmogen such as barium chloride (0.25 mg./ml.),acetyl choline chloride (1.0 mcg./ml.), etc., are established, the testcompound is added and the response to the spasmogen, in the presence ofthe test agent, again determined. Test compound effect is measured asthe percentage reduction in the response to the spasmogen, in thepresence of the test compound, from the mean control response. A minimumof four trials is obtained with each of two to five differentconcentrations of the test compound. The data are expressed in log doseresponse curves and estimates made therefrom of the EC (concentrationcausing 50% reduction in response of the tissue to the spasmogen). Ingeneral, the elfect of compounds identified by Formula I on the rabbitileum is similar to papaverine, a well-known smooth muscle relaxant. Asmight be expected, certain of the compounds are more active than others.For example, 3-[ [N-(S methyl-l-pyrrolin-Z-yl)anilino] methyl] indolehydrochloride is 1.4 times more potent than papaverine while3-[[N-(l-pyrrolin-2-yl)anilino] methyl]indole hydrochloride is from 0.5to about 0.8 as potent as papaverine. Other compounds of particularinterest are N- benzyl-N'-tert.-butyl-N-phenylformamidine hydrochlorideand N-tert.-butyl-N-phenethyl-N-phenylformamidine hydrochloride whichcompared to papaverine are 6 to 16 and 5 times as potent respectively.

Another in vitro test measuring the smooth muscle relaxant properties ofthe compounds of the present invention employs the guinea pig isolatedtracheal spiral and is carried out essentially as described by Lish, etal., J. Pharmacol. Exp. Therap., 129, 191 (1960). As illustrative of theactivity of the compounds of the present in vention in this test therecan be mentioned 3-[(N-1-pyrrolin-2-yl-p-anisidino)methyl]indolehydrochloride which is about 1.7 times as potent as aminophylline.

Smooth muscle relaxant properties of the compounds of the presentinvention can be demonstrated in vivo in the dog. In this test a dog isanesthetized with pentobarbital-sodium and routinely arranged forrecording of intestinal smooth muscle activity. (Goodman and Gilman, ThePharmacological Basis of Therapeutics, 2nd ed., The McMillan Co., 1960,New York). Intravenous administration of the compounds of the presentinvention identified by Formula I and Formula II generally producemarked intestinal smooth muscle relaxant at doses ranging from 1 to 10mg./kg. body weight.

Intestinal smooth muscle relaxant activity can also be measured in an invivo cat preparation. In this test, a balloon is inserted through asmall incision in the stomach of an anesthetized cat to a point about 10cm. down the duodenum and intralumenal intestinal pressure changesrecorded. A solution or suspension of the test agent is administeredintraduodenally about 2 cm. beyond the balloon placed for recordingintraduodenal pressure in volume doses of 1 ml./kg. body weight. Thismeans of administration mimics oral administration. Various doses of thetest agent are administered and an inhibitory dose which suppressesintestinal relaxation by 50% of maximum is determined. This value isdesignated the 113 N- benzyl-N-tert.-butyl N phenylforamidinehydrochloride compared to papaverine is about 1.5 times as potent inthis test.

As a bronchodilating agent3-[(N-l-pyrrolin-2-yl-panisidino)methyl]indole hydrochloride is ofparticular interest. In the histamine challenged guinea pig aerosoltest, refer to Turner, Screening Methods in Pharmacology, page 214(1965) (Academic Press, New York), this com- 7 pound is about 1.4 timesas potent as aminophylline when administered orally.

The compounds of Formula I exhibit anti-inflammatory activity asdemonstrated by the ability to inhibit formation of the local edemawhich forms on plantar injection of carrageenin into .the foot of a rat.This test is performed on adult rats of either sex using a group of tenanimals as a mom-medicated control and another group of ten which istreated orally with the test compound min. prior to the induction ofedema. Edema is induced by the plantar injection of 0.1 ml. of 0.5%solution of carrageenin to the right hind foot. The left hind foot istreated similarly with 0.1 ml. of 0.9% saline. Four hours later thevolume of each hind foot is determined plethysmographically by measuringthe volume of mercury displaced. The amount of edema is expressed as apercent increase in volume of the carrageenin-injected foot over thesaline-injected foot. The percent inhibition of edema is calculated bydividing the mean percent increase in the edema of the carrageenin feetof the medicated group by the mean increase in the non-medicated groupmultiplied by 100. At a dose of 100 mg. per kg. of body weight, thecompounds of Formula I generally produce from about to inhibition ofedema.

The following examples illustrate the best mode contemplated forcarrying out the present invention. They are merely illustrative and arenot to be construed as limiting the scope of the claims in any mannerwhatsoever.

8 Examples 12l.-General procedure for the preparation of N-phenylamidines Phosphorus oxychloride (0.1 mole) is added in one portion to astirred mixture of an N-substituted aniline (0.1 mole) and theappropriate carboxamide (0.1 mole) in ml. of 1,2-dichloroethane. Afterstirring the reaction mixture for a 16 hr. period, it is poured intocrushed ice and 100 m1. of 20% sodium hydroxide. The dichloroethanelayer is separated and extracted with 100 ml. of 1.5 N hydrochloric acidand then with 100 ml. of water. The acidic aqueous portion is made basicwtih 20% sodium hydroxide solution providing an oil which is taken up inether. The etherealextract is dried over magnesium sulfate and thenconcentrated to provide the N-phenyl amidine product which is purifiedby distillation through a short path (ca., 10 cm.) column at reducedpressures.

The N-phenyl amidine free base is converted to the hydrochloride salt bydissolving in ethanol, acidifying the ethanolic solution with ethanolichydrogen chloride and adding anhydrous ether until the hydrochloridesalt precipitates from the solution.

Representative N-phenyl amidines prepared according to the hereinabovedescribed procedures are enumerated in Table I. Table II reportsanalytical values and major infrared absorption peaks of the N-phenylamidine products listed in Table I.

TABLE I.N-PHENYL AMIDINES EL Reamnts Base, B.P., o./ fi f No. Anlllnoamidine product Amine Carboxamide mm. Hg (corr.)

1 Nggzaggfigyilg-phenethyl-N-pheny1formamidine N-phenylphenethylamine.N-tert-butyliormamide 2--"- gi e sg -gg ggt--b tyl-N-p eny o d ne -p y by a '-is p1-opyl-N-(l-phenylethyl)formamidine....; Ng tm r ig l- -plaijg f g 4"-.- 2-(N-phenylbenzylamino)-1-pyrrollne hydrochloride..-N-phenylbenzylamine 2-pyrr0lidin0ne ugf j fg-g 33 5 5-l i t hg-g -ggheny benzylamino)- -pyr o1ine y -py idinone..{iifii iog 6 ,iggg gfifig-ph nv min -p -fl gfi C. 7 2-glighggylphenethylamlno)-1-pyrro1ine hydro-N-phenylphenethylamine- 2-pyrro1idinone 1 :gJ 3 /o %g9 5 8 fi gghg-g -gge uy p nethvlamino)- -pv ro1 ne y -py d none. ,igg sgg sgf g p y p -pyimt v "ggiggggg ggggfiggggf "capmmtam }20s.5-209 5 113,igfiayaigo-2-(N-phenylbenzylamino)pyridine N -phenylbenzylamine....-6-valero1actam ngl tnii ymleggg b82548; 5 123,igtgfggrglsrggggg%ghenylbenzylamino)-2H- n fi-capr l'w m b94498iggg'ggfigfigfggggl? ekewthlomorphonne ggz-gggg-g pm... -aau eeaueageeazeeaa. -tzaiaua 15..- 2%- -g $gg p n m n l- -p n Nggg gg n b- 16.-.-l -g f -g ggg ep y y a l- -py ne Nm rg A-d c -----d uggo ltieg-gmitetumeaaaae ineteen. --tlthft%z 18.---- 2-l fiig gc g g-( -t y )ani nlfi-m t y atg e o-N-t eny -----d0 team-ateieaaaa geeseeaee. {re-teas.late-s.) 2 g gggg g f y n n i t y -py -fi ggrn- -c -.-.-d }17L5 177 -gggg g gg g ggegi 3-ketom0rpho1ine TABLE III--Contln-ued Product Examplenumber X Y A Reactants 29 m-CHaO p-CH= CHN-(3,4-dlmethoxyphenyl)-benzylamine and 5,5-dimethy1-2-pyrr0lidlnone.

30 H H C H N-phenylbenzylamlne and 5,541(n-butyD-Z-pyrrolldlnone.

II-ClHg 31.... H H N-phenylbenzylamlne and S-n-butyl-Z-pyrrolldlnonex-7l-C 4H1) Example 32.Tablets The N-phenyl amidines of the presentinvention are compounded into tablets according to the followingexample.

Material: Amount g.

methyl 2 (N phenylbenzylmino)-1- pyrroline hydrochloride 56.8 Magnesiumstearate 1.3 Corn starch 12.4 Corn starch pregelatinized 1.3 Lactose188.2

Example 34.-3-[(N-1-pyrrolin-2-yl-p-anisidino)methyl] indolehydrochloride Phosphorus oxychloride (1.53 g., 0.01 mole) is added inone portion to a stirred mixture of 3-(p-anisidinomethyl) indole (2.52g., 0.01 mole) and triethylamine (1.01 g., 0.01 mole) in 30 ml. of1,2-dich1oroethane. After stirring the reaction mixture for a 3 hr.period, it is poured into a mixture of crushed ice and 50 ml. of 10%sodium hydroxide. The dichloroethane layer is separated and extractedwith 100 ml. of 0.75 N hydrochloric acid. The acidic aqueous isextracted first with ether, made basic with sodium hydroxide, and thenextracted with ether. After drying over magnesium sulfate, the etherealextract is concentrated to provide 1.3 g. of residue which crystallizedfrom ethanol yields a basic substance melting at 135138 C.

A 7.1 g. sample of material obtained according to the hereinabovedescribed procedure is taken up in ethanol and acidified with ethanolichydrogen chloride to provide a hydrochloride salt. The ethanol solventis removed under vacuum and the residue thus obtained suspended inbenzene and slowly refluxed permitting the benzene mixture to distilltherefrom. Distillation is continued for a period of from 4 to 5 hrs.during which time additional benzene is added as needed. This provides7.13 g. of hydrochloride salt melting at 165-175 C. This fraction isfurther purified by first triturating with hot acetone and thencrystallizing the acetone insoluble product from isopropanol-ether. Onstanding, the acetone mother liquors provide additional product which isalso crystallized from isopropanol-ether. The isopropanol-ethercrystallized fractions are combined and recrystallized fromethanol-ether to yield 1.23 g. of analytically pure 3-[(N-1-pyrrolin-2-yl-p-anisidino)methyl]indole hydrochloride as a white solid, M.P.176177 C. (corn).

Analysis.Calcd for C H N -HCl (percent): C, 67.50; H, 6.23; N, 11.81;Cl, 9.96. Found (percent): C, 67.73; H, 6.03; N, 11.64; Cl, 9.96.

Infrared (0.5% KBr cm.- 3160, 1660, 1510, 1310, 1260, 1040, 850, 750.

NMR 6 (p.p.m.) (CDCI tetramethylsilane ref.): 3.78 (s, 3H), 5.31 (s,2H), 3.94 (m, 2H). (D 0, HDO-4.70 p.p.m. ref.): 3.52 (s, 3H); 4.80 (s,2H); 357 (m, 2H).

Example 35 .3-[ [N-( l-pyrrolin-Z-yl) anilino] methyl] indolehydrochloride Phosphorus oxychloride (7.67 g., 0.05 mole) is added inone portion to a stirred mixture of 3-(ani1inomethyl) indole (11.1 g.,0.05 mole), 2-pyrrolidinone (4.26 g., 0.05 mole) and triethylamine (5.06g., 0.05 mole) in ml. of 1,2-dichlor0ethane at ice bath temperature.Stirring is continued at that temperature for 15 min. and then at roomtemperature for about 16 hr. After quenching in crushed ice and aqueoussodium hydroxide, the reaction mixture is filtered providing 2.5 g., ofsolid free base M.P. -1 17 C. The filtrate is worked up according to themethod of Example 34 by extracting the dichloroethane layer withhydrochloric acid and subsequently extract with ether and then makingbasic with sodium hydroxide. Ether extraction of the basic aqueousmixture with ether and concentrating the dried ethereal extract affordsa second free base fraction, 4.1 g., melting at 118-- 120 C. The freebase fractions are combined and a 5.1 g. sample converted to thehydrochloride salt in ethanol by treatment with ethanolic hydrogenchloride. Concentration of the acidic ethanolic solution provides aresidue which is taken up in water and filtered from a small amount ofsolid. The filtrate is cooled and made basic with 10% aqueous sodiumhydroxide affording the free base which is collected, 3.1 g., M.P.118120 C. The reprepared freebase is then converted to the hydrochloridesalt in the usual manner in ethanol by treatment with ethanolic hydrogenchloride. Addition of ether to the ethanolic solution yieldsanalytically pure 3- [N-(1-pyrrolin-Z-yl)anilino]methyl]indolehydrochloride, 2.6 g., M.P. 163.5166.5 C. (corr.)

Analysis.Calcd for C H N -HCl (percent): C, 70.03; H, 6.19; N, 12.90;Cl, 10.88. :Found (percent): C, 70.03; H, 6.12; N, 12.70; Cl, 10.62.

Infrared (0.5% KB! cm.- 3180, 1670, 1600, 1480, 1450, 1320, 750, 700.

NMR 6 (p.p.m.) (D 0, HBO-4.70 ref.): 3.65 (m, 2H); 3.17 (m, 2H); 4.86(s, 2H).

13 Example 36.--3-[ [N-(S-methyl-l-pyrrolin-Z-yl)-panisidino1methyl1indole hydrochloride Phosphorus oxychloride (3.06 g.,0.02 mole) in 10 ml. of 1,2-dichloroethane is added dropwise in 20 min.to a solution of 3-(p-anisidinomethyl)indole (5.04 g., 0.02 mole),-methyl-2-pyrrolidinone (1.98 g., 0.02 mole) and triethylamine (2.02 g.,0.02 mole) held at a temperature of about 3 C. When the addition iscomplete, the mixture is stirred at 3 to 4 C. for 5 hr. and thenfiltered to provide 2.4 g. solid which is crystallized from wateraffording 1.02 g., M.P. 184-187 C. This fraction is combined with anadditional 1.81 g. fraction obtained as hereinabove described andcrystallized from ethanol to furnish analytically pure3-[[N-(S-methyl-l-pyrrolin-2-yl)-p-anisidino] methyHindolehydrochloride, M.P. 181.'5-183.5 C. (corr.)

Analysis.-Calcd for C H N -HCl (percent): C, 68.19; H, 6.54; N, 11.36;Cl, 9.58. Found (percent): C, 68.03; H, 6.60; N, 11.29; Cl, 9.58.

Infrared (0.5% KBr cmr 3160, 1660, 1510, 1450, 1300, 1250, 750.

NMR 6 (p.p.m.) D 0, HUG-4.70 ref.): 3.60, 3.62 (ss, 3H total); 1.20,1.39 (dd, 3H total, 6.5 Hz); 4.85, 4.92 (ss, 2H total) Example 37.3-['N- 5-methyl-1-pyrrolin-2-yl)- anilino]methyl]indole hydrochloridePhosphorus oxychloride (7.67 g., 0.05 mole), 3-(anilino-methyl)indo1e11.1 g., 0.05 mole), 5-methyl-2-pyrrolidinone (4.96 g., 0.05 mole) andtriethylamine (5.06 g., 0.05 mole) in 100 ml. of 1,2-dichloroethanereacted according to the method of Example 35 provides a total yield of7.55 g. of the product as the free base. A 5.5 g. sample of the freebase is converted to the hydrochloride salt in the usual manner inethanol with ethanolic hydrogen chloride. Addition of ether to theacidified ethanolic solution afiords on standing 3.4 g. of analyticallypure 3-[[N-(5-methyl-1-pyrrolin-2 yl)anilino]methyl]indolehydrochloride, M.P. 172.5174 C. (corr.)

Analysis.--Calcd. for c,,H-,,N,-Hc1 (percent): C, 70.68; H, 6.53; N,12.36; Cl, 10.43: Found (percent): C, 70.41; H, 6.56; N, 12.66; Cl,10.25.

Infrared (0.5% KBr cm.- 3160, 1650, 1590, 1490, 1450, 740, 700.

NMR 5 (p.p.m.) (D 0, HBO-4.70 ref.): 1.10, 1.35 (dd, 3H total, 6.4Hz.);4.82, 4.95 (ss, 2H total).

Example 38.-3-[ (N- l-pyrrolin-Z-yl] anilino)methyl]- l-methylindolehydrochloride Phosphorous oxychloride (4.6 g., 0.03 mole),3-(anilino-methyl)-1-methylindole (7.1 g., 0.03 mole), 2-pyrrolidinone(2.55 g., 0.03 mole) and triethylamine (3.04 g., 0.03 mole) in 75 ml. of1,2-dichloroethane are reacted according to the procedure of Example 35.The reaction mixture is quenched in 100 ml. of 10% sodium hydroxide andice and the organic layer separated therefrom. The organic layer isextracted first with 100 ml. of 1.5 N hydrochloric acid and then 100 ml.of water. The combined extracts are washed with ether, made basic withsodium hydroxide, extracted with ether and the ethereal extract driedover magnesium sulfate and concentrated under reduced pressure toprovide 6.6 g. of a residual oil which on trituration with ether forms asolid. Crystallization from Skellysolve B yields 4.2 g. of 3-[(N-[l-pyrrolin 2 yl]anilino)methyl]-1 methylindole as the free base, M.P.95-97 C. A 2.2 g. sample of the free base is taken up in ethanol andacidified with ethanolic hydrogen chloride and the solution concentratedunder reduced pressure. The residue thus obtained is refiuxed withbenzene permitting the benzene solution to slowly distill. On standing,1.7 g. of analytically pure 3- [(N-[1-pyrrolin-2-yl]anilino)methyl] 1methyindole hydrochloride, M.P. 150.5-154.5 C. (dec.) (corr.) isobtained.

Analysis.Calcd for C H N,.HCl (percent): C, 70.68; H, 6.53; N, 12.36;Cl, 10.43. Found (percent): C, 70.66; H, 6.69; N, 12.20; Cl, 10.44.

Infrared (0.5% KBr cm.- 3000, 1650, 1590, 1500, 1320, 750, 710.

NMR 6 (p.p.m.) (CDC1 tetramethylsilane ref.): 2.39 (t, 2H, 6.7 Hz.);1.79 (p, 2H); 3.25 (t, 2H, 6.8 Hz.); 4.81 (s, 2H); 3.78 (s, 3H).

Example 39.--3-[ (N-(5,5-dimethyl-1-pyrrolin-2-yl) anilino]methyl]indolehydrochloride Phosphorus oxychloride (7.67 g., 0.05 mole) in 20 ml. of1,2 dichloroethane is added rapidly to 3 (anilinomethyl)indole (11.1 g.,0.05 mole), 5,5-dimethyl 2- pyrrolidinone (5.66 g., 0.05 mole) andtriethylamine (5.06 g., 0.05 mole) in ml. of 1,2-dichloroethane at icebath temperature. After stirring the mixture for about 15 min., the icebath is removed and stirring continued at room temperature for 16 hr.Workup of the reaction mixture is as follows. The mixture is quenched inml. of 10% sodium hydroxide and crushed ice and the organic layerseparated. The organic layer is extracted with 100 ml. of 1.5 Nhydrochloric acid and then with 100 ml. of water. After washing thecombined extracts with ether and making basic with 10% sodium hydroxide,a solid precipitates which is collected and crystallized from ethylacetate, yield 3.2 g., M.P. 124-126 C. of free base product. Thedichloroethane fraction is dried over magnesium sulfate and concentratedin vacuum and the residue (10.4 g.) triturated with water and filtered.The aqueous filtrate is made basic with sodium hydroxide providing asecond free base fraction, yield 3.1 g., M.P. 125-127 C. The two freebase fractions are combined, dissolved in ethanol and treated withethanolic hydrogen chloride affording 3.7 g., M.P. -185.5 C. (dec.)(corr.) of analytically pure 3-[(N-(5,5 dimethyl-l-pyrrolin-2-yl)anilino] methyl] indole hydrochloride.

Analysis.-Calcd for C H N .HCl (percent): C, 71.27; H, 6.84; N, 11.87;Cl, 10.02. Found (percent): C, 71.45; H, 6.81; N, 11.84; Cl, 9.93.

Infrared (0.5% KBr cmr' 3120, 1650, 1590, 1500, 1460, 760, 710.

NMR'fi (p.p.m.) (D 0, HBO-4.70 ref.): 1.28 (s, 6H); 4. 87 (s, 2H).

Example 40.'3-[ [N-(5,5-dimethyl-1-pyrrolin-2-yl)-p'-anisidino]methyl]indole hydrochloride Phosphorus oxychloride (1.53 g.,0.01 mole), 3 (panisidinomethyDindole, (2.52 g., 0.01 mole),5,5-dimethyl 2 pyrrolidinone (1.13 g., 0.01 mole), and triethylamine(1.01 g., 0.01 mole) in 50 ml. of 1,2- dichloroethane is reactedaccording to the procedure of Example 36. After standing for 6 hr. atice bath temperature, the reaction mixture is filtered affording thecrude hydrochloride salt (1.45 g.) of the product, M.P. 188- 191 C. Thedichloroethane filtrate is made basic with 10% sodium hydroxide,separated, dried over magnesium sulfate, acidified with ethanolichydrogen chloride, and concentrated under reduced pressure. Tritnrationof the residue thus obtained with acetone yields a second crop of thehydrochloride, (0.76 g.), M.P. 19l194 C. The hydrochloride fractions arecombined and converted to the free base (M.P. 83-85 C.) in the usualmanner by dissolving in water and making basic with sodium hydroxidefollowed by extraction with ether. The hydrochloride salt is repreparedby taking the free base up in ethanol and acidifying with ethanolichydrogen chloride to provide analytically pure 3-[[N-(5,5-dimethyl-1-pyrrolin-2- yl) p anisidino]methyl]indolehydrochloride, M.P. 188.5190.5 C. (dec.) (corr.).

Analysis.Calcd for C H N .HCl (percent): C, 68.82; H, 6.83; N, 10.95;Cl, 9.23. Found (percent): C, 68.69; H, 6.77; N, 10.79; Cl, 9.36.

Infrared (0.5% KBr cmr 2980, 1650, 1510, 1450, 1260, 1180, 1040, 750.

NMR 6 (ppm) (DMSO-d tetr'amethylsilone ref.): 3.72 .(s, 3H); 1.50 (s,6H); 5.27 (s, 2H); 11.33, (broad s, 1H).

Example 41. 3 [[4-methoxy-2-methyl-N-(l-pyrr0lin-2- yl) anilino] methyl]indole hydrochloride Phosphorus oxychloride (7.7 g., 0.05 mole) in ml.of 1,2-dichloroethane is added rapidly to a stirred mixture ofN-(3-indolylmethyl)-4-methoxy-2-methylaniline (13.3 g., 0.05 mole),2-pyrrolidinone (4.3 g., 0.05 mole) and triethylamine (5.1 g., 0.05mole) in 120 ml. 1,2-dichloroethane at ice bath temperature. After theaddition is complete, the cooling bath is removed, the mixture stirredat room temperature for a 16 hr. period, and then quenched in 200 g. ofcrushed ice and made basic with aqueous sodium hydroxide. Extraction ofthe organic layer with 10% aqueous hydrochloric acid, washing theaqueous extract with ether and then making basic with aqueous sodiumhydroxide provides a gummy substance which is collected. This materialis extracted with ether, the ethereal extract dried over magnesiumsulfate and concentrated provides a residue which is dissolved in 20 ml.of ethanol and acidified with ethanolic hydrogen chloride. Dilution ofthe acidified solution with ether yields 2.34 g. of analytically pure 3[[4methoxy-2-methyl-N-(1-pyrrolin-2-yl) 16 anilino]methyl]indolehydrochloride, M.P. 178-180 C. (corn) Analysis.-Calcd for C H N .HCl(percent): 0,

68.18; H, 653; Cl, 9.65; N, 11.35. Found (percent): C,

67.92; H, 6.46; Cl, 9.72; N, 11.18.

Infrared (0.5% KBr cm. 3450, 3200, 1660, 1510, 1460, 1320, 1240, 750.

NMR 6 (ppm) (DMSO-d tetramethylsilene ref.): 3.73 (s, 3H); 1.89 (s, 3H);5.23 (s, 2H).

Examples 42-53 TABLE IV.ADDITIONAL N-PHENYL AMIDINES a m i R III 4Example number X Y All: R R A 42 H H -CH:- H Br U Reactants:3-(anillnomethyl)-5-bromolndole and 2-pyrrolldlnone 43 p-CH;O H -CH2- HBr Same as above.

Reactante: 3-(p-methoxyanillnomethyl)-5-bromoindole and 2-pyrro1idinone44 H H CH:- I H QHiO Do.

Reactants: 3-(anilinomethyl)-5-methoxyindole and 2-pyrrolidinone 451DCH:O H CH2- H CHaO D0.

Reactanta: 3-(p-(ethoxyanilinomethyl)-5-methoxyindole and2-pyrrolidinone 46 H H CH: CH (CH3) H Do.

Reactama: 3-(anilinomethy1)-1-isopropy1lndole and 2-pyrrolindinone 47m-CH; p-CH; CH2 H H Do.

Reactants: 3-(m,pdhnethylanilinomethylfindole and 2-pyrro1idinone 48 H H-CH2 H H OW Reactants: 3-(anilinomethyDindole and 3-ketomorpholiue 49 HH C H:- H H S] N Reactants: 3(anillnomethy1)indole andB-ketothiomorpholine 50 H H -CH H H CH=NCH;

' Reactanta: 3-(anilinomethyDlndole and N-methylformamide 51 H H OH2- HH CH=NCH(CH;);

Reactanta: 3-(anllinomethyl)lndole and N -isopropyltonnamide 52 H H--CH2- H -CH=NC (CH1);

Reactanta: 3-(anillnomethy1)indo1e and N -tert.-butyltormamide 53 H H-CHCH2 H Reacianta: 3-(anilinoethyl)lndole and Z-pyrrolidinone Example54.3-[ [2- (p-methoxyphenylimino) -1-pyrrolidinyl]methyl]indolehydrochloride The mother liquors of the various fractions obtained fromthe purification of 3-[(N-1-pyrrolin-Z-yI-p-anisidino) methyl]indolehydrochloride in Example 34 are combined and concentrated under reducedpressure. Water and ether are added to the residue thus obtained and themixture basified with aqueous sodium hydroxide. The ether layer isseparated, dried over magnesium sulfate, and concentrated yielding basicmaterial which is taken up in ethanol, refluxed for about 2 hr.,concentrated and the residue then crystallized from ethyl acetate. Thehydrochloride salt of this material is prepared in the usual manner inethanol with ethanolic hydrogen chloride. Addition of ether to theacidified mixture precipitates the solid hydrochloride salt which istaken up in ethanol, treated with decolorizing charcoal and diluted withether to yield 1.23 g. of analytically pure3-[[2-(p-methoxyphenylimino)-1-pyrrolidinyl] methyl]indolehydrochloride, M.P. 177-17 8.5 C. (corr.) characterized by the formula:

CHzT

Analysis.Calcd for C H N .HCl (percent): C, 67.50; H, 6.23; N, 11.81;Cl, 9.96. Found (percent): C, 67.20; H, 6.36; N, 11.59; Cl, 9.87.

Infrared (0.5% KBr cmf 3160, 1660, 1510, 1440, 1300, 1240, 1030, 750.

NMR 6 (p.p.m.) (D 0, HD0470 ref.): 3.91 (s, 3H); 4.98 (s, 2H) 3.69 (m,2H).

Example 5 5 .3-[ (Z-phenylaminol-pyrrolidinyl methyl] indole Phosphorusoxychloride (7.67 g., 0.05 mole), 3-(anilinomethyl)indole (11.1 g., 0.05mole), 2-pyrrolidinone (4.26 g., 0.05 mole) and tn'ethylamine (5.06 g.,0.05 mole) in 100 ml. of 1,2-dichloroethane reacted according to theprocedure of Example 35 provide a total of 6.4 g. of crude 3 [[N-(1-pyrrolin-2-yl)anilino]methyl]indole as the free base. The crude freebase is taken up in ethanol and refluxed for 6 hr., treated withdecolorizing charcoal and filtered. Concentration of the ethanolfiltrate to about 20 ml. provides on standing a solid which crystallizedfrom ethanol affords 2.75 g. of analytically pure3-[(2-phenylimino-l-pyrrolidinyl)methyl]indole, M.P. 150-151" C. (corn),characterized by the formula:

Analysis.Calcd for C H N (percent): C, 79.14; H, 6.29; N, 14.57. Found(percent): C, 79.19; H, 6.21; N, 14.41.

Infrared (0.5% KBr cm.- 3400, 3060, 1640, 1600, 1470, 1290, 1260, 1240,760.

NMR 6 (p.p.m.) (CDCl tetramethylsilane ref.): 2.37 (t, 2H, 6.6 Hz.),1.74 (p, 2H); 3.17 (t, 2H, 6.6 Hz); 4.77 (s, 2H); 8.62 (broad s, 1H).

Example 56.3-[ [2-(p-methoxyphenyl)imino]-5-methyll-pyrrolidinyl]methyl]indole hydrochloride An aqueous solution of3-[[N-(5-methyl-l-pyrrolin-2- yl)-p-anisidino]methyl]indolehydrochloride (4.75 g.) ob- Analysis.-Calcd for C H N .HCl (percent): C,68.19; H, 6.54; N, 11.36; Cl, 9.58. Found (percent): C, 68.47; H, 6.52;N, 11.37; Cl, 9.20.

Infrared (0.5% KB! cm.- 3160, 1650, 1520, 1460, 1300, 1250, 750.

NMR 6 (p.p.m.) (CDCl tetramethylsilane ref.): 3.76 (s, 3H); 4.22, 6.00(dd, 2H, 15.4 Hz.); 10.92 (broad s, 1H); 3.67 (m, 2H); 1.85 (m, 2H);3.65 (m, 1H); 1.15 (d, 3H, 6.4 Hz.).

Example 5 7.-3- (S-methyI-Z-phenylimino-l-pyrrolidinyl) methyl] indoleThe 6.1 sample of 3-[[N-(S-methyl-l-pyrrolin-Z-yl) anilino]methyl]indoleas a free base, M.P. 88-92 C., is heated at 180 C. in an oil bath for 2hr. under nitrogen. The cooled pyrrolized product is extracted with fivem1. portions of Skellysolve B. On standing, the Skellysolve B extractyields 3.54 g. of a crystalline product M.P. 134 C. Crystallization ofthis material from benzene-cyclohexane provides analytically pure 3-[(5-methyl-Z-phenylimino-l-pyrrolidinyl)methyl] indole, M.P. 136.5441 C.(corr.), characterized by the formula:

AH. L

Analysis.-Calcd for c H N (percent): C, 79.17; H, 6.98; N, 13.85. Found(percent): C, 79.17; -H, 7.06; N, 13.78.

Infrared (0.5% KBr cm.- 3400, 3160, 2980, 1630, 1590, 1460, 1420, 1240,790, 750, 700.

NMR 6 (p.p.m.) (CDCI tetramethylsilane ref.): 4.19, 5.43 (dd, 2H, 15.2-I-lz.); 8.70 (broad s, 1H); 1.15 (d, 3H, 6.2 Hz.); 3.37 (sextet, 1H).

Example 58.-Preparation of additional iminopyrrolidinylindoles Accordingto the procedure described above in Examples 54-57, preferably that ofExample 55, the following N-phenylamidines:

3-[ (N- [5,5-dirnethyl-l-pyrrolin-Z-yl] anilino) methyl] indole, 3-[ [N-(5,5-dimethyl-1-pyrrolin-2-yl) -p-anisidino] methyl] indole,

3-[ [4-methoxy-2-methyl-'N-( l-pyrrolin-Z-yl) anilino] methyl]indole,3-[ [N- 1-pyrrolin-2-yl) anilino] methyl] -1-benzylindole,

can be arranged on heating to produce: 3-[(2-phenylimino-l-pyrrolidinyl) methyl1-1-methylindole,

3-[ (5,5-dimethyl-2-phenylimino-1-pyrrolidinyl)methyl] indole,

3-[ [2-[ p-methoxyphenyl) imino] -5 ,5 -dimethy1- l-pyrrolidinyl]methyllindole,

methyl]indole,

3-[ Z-phenylimino-l-pyrrolidinyl) methyl] -l-benzylindole.

What is claimed is: 1. A compound selected from the group consisting ofN-phenyl amidines of Formula I @i-Alk-Z Y Formula I and pharmaceuticallyacceptable acid addition salts of compounds of Formula I wherein Alk isan alkylene radical containing 1 or 2 carbon atoms;

X and Y are independently selected from the group consisting ofhydrogen, halogen, trifluoromethyl, lower alkoxy of from 1 to 4 carbonatoms inclusive, lower alkyl of from 1 to 4 carbon atoms inclusive;

Z is

wherein R is hydrogen, lower alkyl or benzyl; R is hydrogen, halogen, orlower alkoxy; and A is C H=NR or wherem wherein n is an integer of 1 to3, R is lower alkyl of from 1 to 4 carbon atoms inclusive,

20 R and R are independently selected from the group consisting ofhydrogen and lower alkyl of 1 to 4 carbon atoms inclusive.

2. The compound of the group defined in claim 1 which is3-[(N-l-pyrrolin-2-yl-p-anisidino)methyHindole and the pharmaceuticallyacceptable acid addition salts thereof.

3. The compound of the group defined in claim 1 which is 3-[[N-(1-pyrrolin-2-y1)anilino]methyl] indole and the pharmaceuticallyacceptable acid addition salts thereof.

4. The compound of the group defined in claim 1 which is3[[N-(S-methyl-l-pyrrolin 2-yl)-p-anisidino]methyl] indole and thepharmaceutically acceptable acid addition salts thereof.

5. The compound of the group defined in claim 1 which is 3-[[N-(S-methyl-l-pyrrolin-Z-yl)anilinoJmethyl]indole and thepharmaceutically acceptable acid addition salts thereof.

6. The compound of the group defined in claim 1 which is 3-[ (N-1-pyrrolin-2-yl1anilino) methyl]-1-methylindole and the pharmaceuticallyacceptable acid addiiton salts thereof.

7. The compound of the group defined in claim 1 which is3-[(N-[5,5-dimethyl-1-pyrrolin 2-yl]anilino)methyl] indole and thepharmaceutically acceptable acid addition salts thereof.

8. The compound of the group defined in claim 1 which is3-[[N-(5,5-dimethy1 1 pyrrolin-Z-yl)-p-anisidino] methyl]indole and thepharmaceutically acceptable acid addition salts thereof.

9. The compound of the group defined in claim 1 which is 3-[[4-methoxy-2-methyl-N (l-pyrrolin-2-yl)anilino] methy1]ind01e and thepharmaceutically acceptable acid addition salts thereof.

JOSEPH A. NARCAVAGE, Primary Examiner U.S. Cl. X.R.

260--239 BE, 243 B, 247.5 R, 296 B, 326.9, 329 AM, 347.7, 564 R; 424263,274, 246, 248, 326

